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Modulation of KIF17/NR2B crosstalk by tozasertib attenuates inflammatory pain in rats

Chronic pain is among the most burdensome and devastating disorders affecting millions of people worldwide. Recent studies suggest the role of kinesin nanomotors in development and maintenance of chronic pain. KIF17 is a member of kinesin superfamily that binds to NR2B cargo system via mLin10 scaffolding protein and makes the NMDARs functional at cell surface. NMDA receptor activation is known to induce the central sensitization and excitotoxicity which can be recognized by the glial cells followed by the release of cytokine storm at spinal and supraspinal level leading to chronic pain. In this study, we have investigated the role of aurora kinase in the regulation of KIF17 and NR2B trafficking in the animal model of chronic inflammatory pain. Tozasertib (10, 20, and 40 mg/kg i.p.), a pan aurora kinase inhibitor, significantly attenuates acute inflammatory pain and suppresses enhanced pain hypersensitivity to heat, cold, and mechanical stimuli in CFA-injected rats. Molecular investigations suggest enhanced expression of KIF17/mLin10/NR2B in L4-L5 dorsal root ganglion (DRG) and spinal cord of CFA-injected rats which was significantly attenuated on treatment with tozasertib. Moreover, tozasertib treatment significantly attenuated CFA-induced oxido-nitrosative stress and macrophage activation in DRG and microglia activation in spinal cord of rats. Findings from the current study suggest that tozasertib mediates anti-nociceptive activity by inhibiting aurora kinase-mediated KIF17/mLin10/NR2B signaling.

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S1048 Tozasertib (VX-680) Tozasertib (VX-680) is a pan-Aurora inhibitor, mostly against Aurora A with Kiapp of 0.6 nM in a cell-free assay, less potent towards Aurora B/Aurora C and 100-fold more selective for Aurora A than 55 other kinases. The only exceptions are Fms-related tyrosine kinase-3 (FLT-3) and BCR-ABL tyrosine kinase, which are inhibited by the Tozasertib with both Ki of 30 nM. Tozasertib induces apoptosis and autophagy. Phase 2.

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FLT3 Autophagy Bcr-Abl